1. Field of the Invention
The invention pertains to a process for preparing alpha-anomer enriched 2-deoxy-2,2-difluoro-D-ribofuranosyl sulfonates for use as intermediates in the preparation of known anti-tumor and anti-viral agents.
2. State of the Art
Stereoselective processes for preparing nucleosides involve stereochemical inversion of a furanose sugar at the anomeric position, therefore when .beta.-nucleoside is the desired product, an appropriate sugar intermediate enriched in alpha anomer is preferably used as the substrate in the glycosylation reaction.
Capon, Brian, Chemical Reviews, 69 (4), 440-441 (1969) proposed a mechanism by which methyl ribofuranosides anomerize in methanol but made no mention of conditions under which one anomer might be obtained in preference to another.
Due to the instability of 2-deoxy-D-erythropentofuranosyl sulfonates, they are conspicuously absent from the chemical literature and therefore are rarely used in glycosylation reactions. The most frequently used 2-deoxyribofuranosyl derivative is 1-chloro-2-deoxy-3,5-(di-O-p-toluoyl)-.alpha.-D-erythro-pentofuranose which was first prepared by M. Hofer, Chem. Ber., 93, 2777 (1960). This is because the compound is crystalline exists exclusively in the .alpha. configuration at C-1 position. However, the 2-deoxyribofuranosyl nucleosides prepared from the glycosylation of this .alpha.-chloro derivative with nucleobase are not obtained stereoselectively. Hubbard, et al., Nucleic Acids, 12, 6827 (1984) reported that this .alpha.-chloro derivative anomerizes in organic solvents at ambient temperature and forms the corresponding .beta.-chloro derivative which was primarily responsible for the formation of .alpha.-nucleosides during glycosylation. Hubbard evaluated the anomerization in several solvents and found a solvent that held the anomerization to a minimum so that the desired .beta.-nucleoside was obtained in high yield.
We have found that 1-halo and 1-methanesulfonate derivatives of 2-deoxy-2,2-difluororibofuranose are stable in certain organic solvents. For example, heating a solution of 2-deoxy-2,2-difluororibofuranosyl methanesulfonate of a known anomeric configuration at C-1 position in an inert organic solvent to 130.degree. C. for extended periods of time does not affect the anomeric configuration of the anomer.
There is a need for an anomerization process that provides alpha-anomer enriched ribofuranosyl sulfonates from beta-anomer ribofuranosyl sulfonates.
Accordingly, one object of the present invention is to provide an anomerization process that provides alpha-anomer enriched ribofuranosyl sulfonates from beta-anomer ribofuranosyl derivatives.
Another object of the present invention is to provide an anomerization process that provides alpha-anomer enriched ribofuranosyl sulfonates in high yield.
Other objects and advantages of the present invention will become apparent from the following description of embodiments.